Jin Chunhua, Jeon Yejoo, Kleven Daniel T, Pollock Jennifer S, White John J, Pollock David M
Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia
J Pharmacol Exp Ther. 2014 Nov;351(2):467-73. doi: 10.1124/jpet.114.215566. Epub 2014 Sep 4.
Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl salt-sensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1(+) cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.
实验旨在确定内皮素A（ETA）受体拮抗剂[ABT - 627，阿曲生坦；(2R,3R,4S)-4-(1,3 - 苯并二氧杂环戊烯 - 5 - 基)-1-[2-(二丁基氨基)-2 - 氧代乙基]-2-(4 - 甲氧基苯基)吡咯烷 - 3 - 羧酸]与噻嗪类利尿剂（氯噻酮）联合使用，相较于单独使用任一药物，在代谢综合征啮齿动物模型中降低血压和减轻肾损伤方面是否更有效。雄性Dahl盐敏感大鼠喂食高脂（36%脂肪）、高盐（4%氯化钠）饮食4周。然后将大鼠分成不同组，分别用赋形剂（对照组）、ABT - 627（ABT；每天5毫克/千克，溶于饮用水中）、氯噻酮（CLTD；每天5毫克/千克，溶于饮用水中）或ABT加CLTD进行处理。通过遥测连续记录平均动脉压（MAP）。4周后，ABT和CLTD均显著减轻高血压的发展，而联合用药组相较于单独使用ABT能进一步降低MAP。所有治疗均能预防蛋白尿。CLTD以及ABT加CLTD显著降低了nephrin（足细胞损伤标志物）和肾损伤分子 - 1（肾小管间质损伤标志物）的排泄。无论是否联合CLTD，ABT均显著降低了血浆8 - 氧代 - 2'-脱氧鸟苷水平（一种DNA氧化指标），而单独使用CLTD则无此效果。所有治疗均抑制了肾脏中ED1(+)细胞（巨噬细胞）的数量。血浆肿瘤坏死因子受体1和2仅在ABT与CLTD联合用药组中降低。这些结果表明，ABT和CLTD在代谢综合征模型中具有降压和肾保护作用，两种药物联合使用时效果最佳。这些发现支持了以下假设：联合使用ETA拮抗剂和利尿剂治疗可能为食用西方饮食的代谢综合征患者提供治疗益处。
